Project Summary Abstract Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is still the most common AIDS-defining cancer in HIV-positive individuals, although KS can also occur in HIV-negative individuals. In certain regions of sub-Saharan Africa, KS is the most prevalent cancer. Other immunosuppressed individuals such as transplant patients also develop KS much more frequently than the healthy population. We have previously reported that activation of the PI3K/Akt/mTOR signaling pathway is critical for survival of KSHV-infected cells as well as the survival of KS and PEL tumors. We have reported that KSHV and the K1 and ORF36/vPK viral proteins are important for activating different nodes of the PI3K/Akt/mTOR pathway. Our overarching hypothesis is that KSHV viral proteins, including ORF36/vPK, modulate cellular signaling pathways that are also conducive to transformation. In this application, we propose to determine the mechanisms by which ORF36/vPK can modulate cell proliferation, signaling, and angiogenesis pathways. We will also explore novel host factors that are critical for survival and proliferation of KSHV infected cells. The proposed studies will provide significant, and biologically relevant insights into the functions of viral signaling proteins, and may yield a new target for anti-KSHV therapies.